Tolerance to the antinociceptive and antiexudative effects of morphine in a murine model of peripheral inflammation

Opioids are used in humans in the management of chronic osteoarticular pains, but the development of tolerance to the analgesic effects after continuous administration is still not well understood. Our aim was to characterize morphine tolerance in a murine model of arthritis that mimics the sequence of events occurring in humans. Inflammation was induced by the intraplantar injection of complete Freund's adjuvant ( CFA) and tolerance by the implantation of a 75- mg morphine pellet. We assessed the antihyperalgesic ( plantar and Randall- Selitto tests), antiallodynic ( Von Frey test), and antiexudative ( Evans blue) effects of morphine, the mu-opioid receptor ( MOR) mRNA levels in dorsal root ganglia ( DRG), and MOR protein levels in DRG and plantar tissue. Inflammation induced plasma extravasation, and it significantly increased the antihyperalgesic effects of morphine ( p < 0.05). Morphine pellet implantation decreased morphine potency in all tests. ED50 values decreased 4.4 and 7.3 times in the absence and presence of inflammation in the plantar test and 2.7 and 5.3 times in the Randall- Selitto test, whereas plasma extravasation decreased 4.2 times. MOR mRNA levels in the DRG were not affected 7 days after inflammation, whereas chronic morphine administration induced a discrete increase ( p < 0.05). MOR protein in the DRG or the paw was unchanged. The results show that inflammation enhances the development of tolerance to the antihyperalgesic and antiexudative effects of morphine. At the molecular level, our results suggest that these effects are not mediated by changes in MOR expression but by other changes in receptor activation/ internalization.